Low temperature chlorination of carbohydrates

ABSTRACT

Disclosed is a method of chlorinating a carbohydrate or derivative thereof, for example, a sucrose-6-ester at the 4,1′, and 6′ positions, with irreversible removal of HCl formed during the reaction to form the chlorinated carbohydrate or derivative thereof, for example, a 4,1′,6′-trichloro-4,1′,6′-trideoxy-6-O-ester of galactosucrose (TGS-6E). The irreversible removal of HCl can be carried out by an irreversible physical process and/or an irreversible chemical process. Sucralose, an artificial sweetener, can be prepared by deesterification of the TGS-6E. The chlorination reaction takes place at low temperatures and the desired chlorinated product is obtained in high yields and in high purities.

CROSS-REFERENCE TO A RELATED APPLICATION

This patent application is a continuation of International PatentApplication No. PCT/US2011/061796, filed Nov. 22, 2011, claiming thebenefit of United States Provisional Patent Application No. 61/416,674,filed Nov. 23, 2010, the disclosures of which are incorporated byreference.

BACKGROUND OF THE INVENTION

Chlorination of carbohydrates and derivatives thereof, such as sugarsand their esters, has been known. For example, sucralose,4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose, is an artificialsweetener with a sweetness intensity many times that of sucrose.Sucralose is a sucrose derivative, made by chlorination of a sucroseester such as sucrose-6-acetate or sucrose-6-benzoate.

Attempts have been made in the industry to improve the reactionconditions, the yield, and/or the reduce the amount of impurities formedduring the chlorination reaction. However, the reaction conditions arestill harsh, e.g., high reaction temperatures and/or long reaction timesare employed. Alternatively, the yields of the trichlorinated ester arelow. In some instances, the reported chlorination reaction conditionsare not reproducible.

For example, U.S. Pat. No. 4,980,463 to Walkup et al. discloses thatwhen sucrose-6-benzoate is chlorinated with phosgene, onlymonochlorinated product is formed within the temperature range of 50° C.to about 70° C. The '463 patent discloses that the reaction mixture maybe maintained at this temperature for at least 1 hour with little or nodi- or higher chlorination occurring.

The '463 patent further discloses that the above monochlorinatedreaction mixture must be heated to a temperature range of 75° C. to 100°C. and preferably 80° C. to 85° C. to effect partial dichlorination ofthe sucrose-6-ester. The '463 patent discloses that at this temperaturelittle or no tri- or higher chlorination occurs and a mixture ofprimarily monochlorinated sucrose-6-esters plus some dichlorinatedsucrose-6-esters results after about 1 hour. The '463 patent furtherstates that maintenance of the reaction mixture at this temperature forlonger periods of time results in a higher degree of conversion ofmonochlorinated sucrose-6-esters to dichlorinated sucrose-6-esters withlittle or no trichlorination observed by silica gel TLC.

The '463 patent further states that in preferred aspects of theinvention, the temperature is increased rapidly, after initiallyattaining 80° to 85° C., to a temperature sufficient to completelyconvert monochlorinated sucrose-6-esters to dichlorinatedsucrose-6-esters, trichlorinated sucrose-6-esters and little or notetra- or higher chlorinated sucrose-6-esters. The '463 patent furtherteaches that the temperatures for this step are usually in the range ofabout 100° C. to about 130° C. and preferably from about 110° C. toabout 125° C. According to the '463 patent, the reaction mixture is heldat this temperature for a period sufficient to maximize trichlorination,e.g., from about 1 hour to about 6 hours, and preferably chlorination ofsucrose-6-ester at 85° C. produces a mixture of chlorinatedsucrose-6-ester products consisting essentially of6′-chlorosucrose-6-ester, 4,6′-dichlorosucrose-6-ester, and 1′,6′-dichlorosucrose-6-ester. According to the '463 patent, the abovemixture must be heated to a temperature not higher than 125° C. for aperiod of time sufficient to produce a chlorinated product consistingessentially of 1′, 4, 6′-trichlorosucrose-6-ester.

The '463 patent states that it takes nearly 5 to 6 hours of totalreaction time to obtain maximum yields of about 60% ofsucralose-benzoate as shown in FIG. 7 of the patent. FIGS. 4 and 5 ofthe '463 patent, disclosing conversion as a function of reaction timewith phosphorous oxychloride, indicate that the sucralose-6-benzoatecontent reaches a maximum at 4 hours at 115° C., and thereafter dropsoff, with concomitant increase in higher chlorinated products. InExample 5, the '463 patent discloses that, when phosphorous oxychlorideis employed as the chlorinating agent, the yield of sucrose-6-benzoateis only 31.9%.

WO 2008/052076 A2 to Ho et al. discloses a process for the preparationof sucralose by the chlorination of sugar with triphosgene. According toHo et al., paragraph [0008], the chlorination reaction mixture is heatedto 110° C. and refluxed at 110° C. for 3 hours. While Ho et al.contemplates at paragraph [0013] that the chlorination reaction may becarried our under vacuum to avoid the oxidation of the reaction mixtureby oxygen in ambient temperature, none of the examples ran the reactionunder vacuum.

United States Patent Application Publication No. 2007/0100139 A1 by Fryreportedly discloses methods for chlorinating sucrose-6-esters toproduce 1′,4,6′-trichlorosucrose-6-esters including providing a reactionmixture in a temperature-controlled vessel at a temperature less thanabout 65° C. (abstract). The methods for chlorinating thesucrose-6-ester according to Fry further include subjecting thechloroformiminium chloride salt, tertiary amide, and sucrose-6-esterreaction mixture to an elevated temperature between about 75° C. and100° C. for a period of time sufficient to produce a chlorinated productmixture of chlorinated sucrose-6-ester products consisting essentiallyof 1′,4,6′-trichlorogalacto-sucrose-6-ester. In one aspect, Fryrecommends maintaining the temperature during chlorination at about 85°C. for about 50 hours to maximize the yield; however, no actual yieldvalue is reported. Fry also teaches that acetic acid may be used toincrease the yield of the trichlorinated sucrose ester. However, thepresent inventors find that some of the assertions made in Fry are notreproducible. The Fry patent application went abandoned for failure toprosecute.

United States Patent Application Publication No. 2007/0207246 A1 by Wanget al. teaches that sugar-6-acetate can be reacted with PCl₅ and DMF toobtain sucralose-6-acetate. Wang et al. asserts at paragraph [0040] thattrichloroacetonitrile can be used as a catalyst for the chlorination andthe temperature of the reaction mixture is raised to 80° C. in 6 hoursand maintained there for 3 hours to obtain sucralose-6-acetate. However,the present inventors experienced a reproducibility issue with thismethod.

In view of the foregoing, there is a desire to have an improved methodof chlorinating carbohydrates or derivatives thereof, particularlysucrose esters.

BRIEF SUMMARY OF THE INVENTION

The invention provides methods of chlorinating sucralose-6-esters andintermediates thereof. Thus, in one aspect, the invention provides amethod of selectively chlorinating a sucrose-6-ester at the 4,1′, and 6′positions with irreversible removal of HCl formed during the reaction toform a 4,1′,6′-trichloro-4,1′,6′-trideoxy-6-O-ester of galactosucrose(TGS-6E), which can be converted to sucralose by known methods. Theirreversible removal can be carried out by an irreversible physicalprocess and/or an irreversible chemical process.

An advantage of the method of the chlorination of the invention is thatit can be performed at a lower temperature than previously reported,thereby avoiding the formation of overchlorinated impurities as well as“charred” intractable organic impurities in the intermediates and/or thefinal product that are often encountered in reactions run at highertemperatures. Removal of HCl also allows the reaction to go nearly to orfully to completion giving higher conversions. The lower temperature,coupled with the higher conversions of the method of the presentinvention, leads to conservation of natural resources as it requiresless energy for each kilogram of TGS-6E—the immediate precursor tosucralose—produced.

Thus, the present invention offers one or more of the followingadvantages: greater selectivity, higher yield, reduced amount ofimpurities, and/or reduced energy consumption during reaction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for chlorinating a carbohydrateor a derivative thereof comprising reacting the carbohydrate orderivative thereof with a chlorinating agent and irreversibly removinghydrogen chloride produced during the chlorination of the carbohydrateor derivative thereof.

In accordance with the invention, any suitable carbohydrate orderivative thereof, which has at least one, two, three, four, five, ormore hydroxyl groups, of which at least one hydroxyl group is availablemay undergo chlorination. The carbohydrate can be a monosaccharide,oligosaccharide or polysaccharide. The oligosaccharide can bedisaccharide, trisaccharide, tetrasaccharide, or a higher saccharide. Anexample of a disaccharide is sucrose. Examples of higher saccharidesinclude starches, cellulose, hemicelluloses, gums, dextrans, gellan,pullulan, scleroglucan, welan, xanthans, agars, algins, carrageenans,furcellarans, pectins, chitins, and chitosans.

In accordance with an embodiment of the invention, the carbohydrate orderivative thereof is a sugar or derivative thereof. Examples ofsuitable sugars include sucrose, maltose, lactose, erythrose, threose,ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose,gulose, idose, galactose, and talose, particularly sucrose.

The carbohydrate or sugar derivative can be any suitable derivative, forexample, an ester, ether, acetal, carboxyalkylate, or amino, or where analdehyde or carbonyl group has been reduced or oxidized to hydroxyl orwhere a hydroxyl group has been removed by reduction or oxidized to acarbonyl or carboxyl group. In an embodiment, the sugar derivative is asugar ester, more particularly a sucrose ester. In an embodiment, thecarbohydrate derivative can also be a nucleoside, e.g., uridine,deoxyuridine, adenosine, deoxyadenosine, guanosine, deoxyguanosine,thymidine, deoxythymidine, cytidine, deoxycytidine, or a nucleotide suchas DNA or RNA. In accordance with the invention, the carbohydratederivative can be one where a carbohydrate molecule is covalently linkedanother molecule, e.g., a polymer molecule.

In accordance with an embodiment of the invention, the sugar ester is asucrose-6-ester and the chlorinated product is chlorinatedsucrose-6-ester, particularly4,1′,6′-trichloro-4,1′,6′-trideoxy-6-O-ester of galactosucrose (TGS-6E).TGS-6E can be prepared by esterification of sucrose. Any suitable estercan be prepared which will be stable to the chlorinating agent that willbe used and which can be hydrolyzed without much difficulty. The estercan be a C₁-C₁₈ aliphatic, C₆-C₁₄ aryl C₁-C ₁₈ aliphatic or C₆-C₁₄ arylcarboxylate ester. Particularly suitable carboxylate esters includelower alkyl, e.g., C₁-C₆ alkyl carboxylates such as acetates andpropionates, and C₆-C₁₀ aryl carboxylates such as benzoate or naphthoateester. The ester can be prepared by acylation of the carbohydrate orsugar using an acylating agent of the relevant acid, and in the case ofcarboxylic acylation, it is an acyl anhydride or acyl halide.Alternatively, the carbohydrate can be esterified by enyl esters. In anembodiment, reaction with enyl esters is effected in the absence ofwater and in the presence of no more than a trace of a base catalyst,for example, in a polar aprotic solvent. For these and other methods ofproduction of esters, see, e.g., U.S. Pat. No. 4,380,476, the disclosureof which is incorporated herein by reference.

In an embodiment, the sucrose ester is sucrose-6-acetate, wherein theacetyl group is placed exclusively at the 6-position. Mono-acylation canbe maximized by controlling the reaction, e.g., by maintaining thesucrose in excess throughout the addition of the acylating agent or byusing very low reaction temperature. Thus, for example, sucrose canacetylated by the use of acetic anhydride and pyridine at a temperaturebelow about −20° C., e.g., −20 to −75° C., in embodiments, from −25 to−45° C.; see, e.g., U.S. Pat. No. 4,380, 476; col. 3, lines 3-37.

In accordance with an embodiment of the invention, the carbohydrate orderivative thereof, particularly, the sugar ester is chlorinated byreacting with a chlorinating agent. Any suitable chlorinating agent canbe employed. In accordance with an embodiment, the chlorinating agent isselected from the group consisting of thionyl chloride, sulfurylchloride, phosgene, phosphorus pentachloride, oxalyl chloride, methanesulfonyl chloride, and bis(trichloromethyl)carbonate.

In accordance with an embodiment, the chlorinating agent is a Vilsmeierreagent having the formula: [XYC=N⁺R₂] Cl⁻, wherein X is hydrogen oralkyl which is optionally substituted with a halogen, alkoxy,thioalkoxy, amido, or cyano; Y is a leaving group; and R is hydrogen,aryl, or C₁-C₁₈ linear or branched alkyl group or C₃-C₁₈ cyclic alkylgroup, each o f which is optionally substituted with halogens, furtheralkyl chains or heteroatoms. For example, in an embodiment, R ishydrogen, aryl, or alkyl, wherein the aryl or alkyl is optionallysubstituted with halogen, alkoxy, thioalkoxy, amido, or cyano.

The Vilsmeier reagent can be obtained for example by reaction of thionylchloride, triphosgene, or any acid chloride with an amide and usedeither as is or pre-reacted with a heteroatomic nucleophile YH to forman alternative comparably reactive reagent. Such a reagent canalternatively be formed prior to use in the chlorination reaction, or itmay be formed in situ or it may be purchased from commercial sources.

In an embodiment, Y is halogen, heteroalkyl or other group capable ofbeing displaced by a heteroatomic nucleophile, tosylate, brosylate,besylate, nosylate, mesylate, alkylfluorosulfonates, triflates,nonaflates, and tresylates, and in an embodiment, Y is halogen.

In a particular embodiment, the method is carried out by employing aVilsmeier reagent wherein X is hydrogen, Y is chloro, and R is methyl.

In accordance with an embodiment, the Vilsmeier reagent can be producedby the reaction of N,N-dialkyl formamide, e.g., N,N-dimethylformamide,or N,N-dialkylacetamide, e.g., N,N-diemthylacetamide, with achlorinating agent, in an embodiment, thionyl chloride.

In accordance with the invention, the chlorination reaction can becarried out in a suitable solvent, polar or non-polar, and in anembodiment, polar solvent, particularly polar aprotic solvent. Examplesof polar aprotic solvents include N,N-dimethylacetamide,N,N-dimethylformamide. N-methyl pyrrolidone, dimethylsulfoxide,sulfolane, tetrahydrofuran, and combinations thereof, particularlyN,N-dimethylformamide. Examples of non-polar solvents include aromatichydrocarbons, halogenated hydrocarbons and combinations thereof.Examples of aromatic hydrocarbons include xylenes, toluene, and diethylbenzene, and examples of halogenated hydrocarbons include1,2-dichloroethane, 1,1-dichloromethane, 1,1,2-trichloroethylene,chlorobenzene, and dichlorobenzenes, and combinations thereof

For example, the sucrose-6-ester and the chlorinating agent are combinedin the solvent at a suitable temperature, for example, between −30° C.and 25° C. During the addition of the chlorinating agent, thetemperature is generally not allowed to rise above about 60° C., and inembodiments, above 50° C. Typically, the temperature is maintained fromabout 0° C. to about 30° C.

The term “irreversibly removing” refers to a process or step wherein thehydrochloride is removed from the reaction mixture such that it is nolonger available to come in contact with, remain in the proximity orvicinity of, set up an equilibrium with, interfere or interact with, oneor more of the components of the reaction mixture. This is distinct fromprocesses such as the use of entrainment or other trapping method forremoving HCl which upon heating or under vacuum releases HCl back intothe system.

In accordance with the invention, at least a portion of the HCl producedduring the chlorination is removed by an irreversible process. Forexample, at least about 10%, at least about 20%, at least about 30%, atleast about 40%, or at least about 50%, or more, of the HCl produced isremoved irreversibly. In an embodiment of the invention, in order forthe chlorination to proceed to completion or close to completion, amajority of, all, or substantially all of the HCl produced during thechlorination reaction is irreversibly, and, in embodiments, completelyor substantially completely, removed from the reaction mixture. Thus,for example, at least about 60%, about 70%, about 80%, about 90%, about99%, about 99.9%, or about 99.99% or even 100%, of the HCl is removedirreversibly.

The irreversible removal process can be an irreversible physical processor an irreversible chemical process or a combination thereof.

In an embodiment, at least a portion of the hydrogen chloride isirreversibly removed by an irreversible physical process. Any suitableirreversible physical process can be employed. For example, theirreversible physical process includes applying vacuum or sonic energyto the reaction mixture, sparging a moisture free gas through thereaction mixture, inducing cavitation into the reaction mixture,distilling off HCl, or a combination thereof The HCl can distill off asa pure component or in combination with one or more other reagents orsolvents, e.g., as an azeotrope.

Alternatively, or in addition, in accordance with an embodiment, all orsubstantially all HCl produced during the chlorination reaction isremoved by an irreversible chemical process. The irreversible chemicalprocess can be one which irreversibly reacts with HCl, such as propyleneoxide, olefins, and the like, to form an inert substance (like ahalocarbon), to bring about the separation and removal of the HCl awayfrom the reaction mixture. Inert substance indicates that the chlorinepresent in the substance is not available for reaction with the sugarderivative.

Herein, irreversible removal, irreversible physical removal orirreversible chemical process removal does not refer to the use ofadsorbents or absorbents in contact with the chlorination reactionmixture to remove the HCl, for example, zeolites, activated carbon orcharcoal, or amine reagents such as monoamines or polyamines whereattractive or van der Waals forces play a role between the adsorbent orabsorber and HCl. In non-physical adsorptive or absorptive processes,the HCl is adsorbed or absorbed by the adsorbent or absorbent; however,the HCl is still present in contact with the reaction medium or in closeproximity to the reactants.

Without wishing to be bound by any theory or mechanism, it is believedthat the HCl present in the reaction medium, even if present adsorbed orabsorbed as in the prior art processes, becomes available to participatein the equilibrium reaction between the substrate to be chlorinated andthe chlorinated product. It is believed that the HCl present in theprior art reaction mixture shifts the equilibrium towards thenon-chlorinated substrate. In contrast thereto, and in accordance withthe invention, the HCl is removed irreversibly from the reaction medium,for example, by an irreversible physical process or by an irreversiblechemical process, thereby shifting the equilibrium towards thechlorinated product essentially completely.

In an embodiment of the irreversible physical process, a vacuum isapplied to the reaction vessel containing the reaction mixture to removethe HCl formed therein. Any suitable vacuum can be applied, for example,from about 0.01 mm Hg to about 750 mm Hg, and in certain embodimentsfrom about 0.1 mm Hg to about 300 mm Hg, and in some embodiments, fromabout 1 mm Hg to about 100 mm Hg. The vacuum can be applied for anysuitable length of time, e.g., from 1 minute to about 6, 8, 10, or 12hours or more, and in certain embodiments, from about 5 minutes to about3 hours, and in some embodiments, from about 30 minutes to about 2hours. The degree of vacuum that is applied will depend on thetemperature of the reaction mixture and the volatility of the solventspresent in the reaction mixture. Less volatile solvents allow theapplication of higher vacuums than more volatile solvents. In some casessolvent distills off and is collected.

In an embodiment, vacuum can be applied to the reaction mixture untilall carbohydrate or derivative thereof, e.g., sucrose ester, has beenconsumed.

In accordance with the invention, the vacuum can be applied when thereaction mixture is being heated or when the reaction mixture hasreached the desired reaction temperature.

In accordance with the invention, HCl produced during chlorination canbe removed by an adsorbent which is located external to the chlorinationreactor. The adsorbent can be placed in a column, tank, or any othertype of scrubbing vessel, and HCl vapors or a mixture of HCl and solventvapors passed through the adsorbent. Thus, the adsorbent contacts thedistillate from the chlorination reactor but not the chlorinationmixture. The adsorbent can be any suitable adsorbent, for example, anadsorbent comprising an acid scavenger.

The temperature of the reaction mixture is then raised and maintained ata high level for a suitable period of time, e.g., for about 1 to about16 hours, typically for about 6, 8, 10, 12, or 16 hours. The reactioncan be carried out at any suitable temperature. In accordance with anembodiment of the invention, the reaction is performed at a temperatureno higher than 100° C., as this is the temperature at whichover-chlorinated by-products begin to form in significant amounts, andin embodiments, no higher than 90° C., and in further embodiments, nohigher than 85° C. In accordance with an embodiment, the highesttemperature that can be maintained is about 50° C. to about 60° C. Incertain embodiments, the highest temperature that can be maintained isabout 75° C. to about 80° C. The reaction mixture can be heated in anysuitable manner including heating ramps and/or spiking of temperature.In embodiments, the reaction can be carried out at temperatures evenhigher than 100° C., for example, 110° C., 120° C., or more for limitedperiods of time. The extent of the reaction can be monitored by anysuitable technique, e.g., TLC and/or HPLC.

One of the advantages of the present invention is that sucralose-6-estercan be produced in high yields and/or high purities, and/or at lowtemperatures and/or at short reaction times. In this regard, the presentinvention is superior to known processes.

In accordance with an embodiment of the invention, even while physicallyor chemically irreversibly removing the HCl produced, e.g., by applyingvacuum, sparging with a moisture free gas, sonicating and/or subjectingthe reaction mixture to chemical methods for reacting HCl toirreversibly form an inert substance, the reaction mixture can bemaintained under a moisture free gas atmosphere. Any suitable moisturefree gas can be provided, e.g., argon, nitrogen, helium, or air. Themoisture free gas is preferably an inert gas or a gas with minimalreactivity to the reactants and/or the products.

Although the method of the invention does not require that an adsorbentor absorber for HCl be included in the reaction mixture where HCl isformed, in an embodiment, such an adsorbent or absorber can beoptionally included in the reaction mixture. For example, the adsorbentor absorber can be an acid scavenger such as zeolites, activated carbon,organic amines, and polymeric resins. For additional examples ofadsorbents or absorbers, see International Patent Publication WO2007/099557 A2, the disclosure of which is incorporated by reference.

After the chlorination reaction, the reaction mixture is quenched. Anysuitable quenching reagent can be used, e.g., a mixture of pyridine andwater or a mixture of aqueous ammonium hydroxide and methanol. Theresulting TGS-6E product is recovered, e.g., by filtering the solutionthrough a bed of adsorbent (e.g., celite), extracting the neutralizedaqueous mother liquor with an appropriate solvent, and concentrated,e.g., by drying under vacuum to a viscous oil. The oil may solidify onstanding in embodiments of the invention.

In accordance with an embodiment of the invention, the yield of thesucralose-6-ester, particularly sucrose-6-acetate, is at least 65%, inembodiments, at least 70%, and in certain embodiments, at least 80%, andin some embodiments, the yield is as high as 90%. In accordance with anembodiment, the yield is between 65 and 80%, which is a major processimprovement over known methods.

In accordance with the invention, the chlorinated sucralose-6-esterisolated by the method is free or substantially free of tar or charredresidues, e.g., tar or charred residues are less than 5% by weight, incertain embodiments, less than 1% by weight, and in other embodiments,less than 0.5% by weight.

In accordance with the invention, the sucralose-6-ester produced by themethod is free or substantially free of over-chlorinated products. Thus,for example, the over-chlorinated products, e.g., tetrachlorinatedsucrose products, are less than 5% by weight, in certain embodiments,less than 1%, and in other embodiments, less than 0.5% by weight.

In accordance with the invention, the sucralose-6-ester produced by themethod is free or substantially free of under-chlorinated products.Thus, for example, the under-chlorinated products are less than 10%,less than 5% by weight, in certain embodiments, less than 1%, and inother embodiments, less than 0.5% by weight. In accordance with anembodiment of the invention, the dichlorinated products are less than 4%by weight, in certain embodiments, less than 0.5%, and in otherembodiments, less than 0.2% by weight.

In accordance with an embodiment, the invention provides a method forchlorinating a carbohydrate or a derivative thereof comprising:

-   -   (i) dissolving the carbohydrate or derivative thereof in a polar        or non-polar aprotic solvent to obtain a solution of the        carbohydrate or derivative thereof;    -   (ii) forming a chlorinating agent in and/or combining a        pre-formed chlorinating agent in a solvent followed by        dissolution of carbohydrate or derivative thereof to obtain a        chlorination mixture;    -   (iii) irreversibly removing all or substantially all of the        hydrogen chloride produced during reaction of the chlorinating        agent with the hydroxy group or groups of the carbohydrate        and/or during chlorination of the carbohydrate or derivative        thereof;    -   (iv) optionally heating the reaction mixture from (iii) under an        inert gas atmosphere to a temperature of 60° C. for a period of        about 2 hours or more; and    -   (v) optionally heating the reaction mixture to a temperature not        more than 100° C., 95° C., or 85° C., for a period of up to 16        hours, to obtain the chlorinated carbohydrate or derivative        thereof.

In accordance with an embodiment, the invention also provides a methodof preparing sucralose comprising de-esterifying the chlorinated sucroseester obtained according to the various embodiments described above. Thesucrose ester can be de-esterified, for example, by alkaline hydrolysisusing sodium methoxide in methanol as shown in U.S. Pat. No. 4,380,476;col. 10, lines 1-22.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing aspects) are to be construed to cover both the singular andthe plural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those embodiments may become apparent to those of ordinary skill inthe art upon reading the foregoing description. The inventors expectskilled artisans to employ such variations as appropriate, and theinventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theaspects appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the invention unless otherwise indicatedherein or otherwise clearly contradicted by context.

The invention covers the following aspects:

1. A method for chlorinating a carbohydrate or a derivative thereofcomprising reacting the carbohydrate or derivative thereof with achlorinating agent and irreversibly removing hydrogen chloride producedduring the chlorination of the carbohydrate or derivative thereof.

2. The method of aspect 1, wherein the carbohydrate or derivativethereof is a sugar or derivative thereof

3. The method of aspect 2, wherein the sugar derivative is a sugarester.

4. The method of aspect 3, wherein the sugar ester is a sucrose-6-ester.

5. The method of aspect 4, wherein the chlorinated product obtained is4,1′,6′-trichloro-4,1′,6′-trideoxy-6-O-ester of galactosucrose (TGS-6E).

6. The method of any one of aspects 1 to 5, wherein the chlorinatingagent is an acid chloride.

7. The method of aspect 6, wherein the acid chloride is selected fromthe group consisting of thionyl chloride, sulfuryl chloride, phosgene,phosphorus pentachloride, oxalyl chloride, methane sulfonyl chloride,and bis(trichloromethyl)carbonate.

8. The method of any one of aspects 1 to 6, wherein the chlorinatingagent is a Vilsmeier Reagent having the formula: [XYC=N⁺R₂] Cl⁻, whereinX is hydrogen, aryl, or alkyl, wherein the aryl or alkyl is optionallysubstituted with a halogen, alkoxy, thioalkoxy, amido, or cyano; Y is aleaving group; and R is hydrogen or alkyl which is optionallysubstituted with halogen, alkoxy, thioalkoxy, amido, or cyano.

9. The method of aspect 8, wherein Y is halogen, heteroalkyl, or a groupcapable of being displaced by a heteroatomic nucleophile .

10. The method of aspect 9, wherein the heteroatomic nucleophile isselected from the group consisting of tosylate, brosylate, besylate,nosylate, mesylate, alkylfluorosulfonates, triflates, nonaflates, andtresylates.

11. The method of aspect 9, wherein Y is halogen.

12. The method of any one of aspects 8, 9, and 11, wherein X ishydrogen, Y is chloro, and R is methyl.

13. The method of aspect 12, wherein the Vilsmeier Reagent which isproduced by the reaction of N,N-dimethylformamide with an acid chloride.

14. The method of aspect 13, wherein the acid chloride is selected fromthe group consisting of thionyl chloride, sulfuryl chloride, phosgene,phosphorus pentachloride, oxalyl chloride, methane sulfonyl chloride,and bis(trichloromethyl)carbonate.

15. The method of any one of aspects 1 to 14, wherein the chlorinationreaction is carried out in a polar or non-polar solvent.

16. The method of aspect 15, wherein the polar solvent is a polaraprotic solvent.

17. The method of aspect 16, wherein the polar aprotic solvent isselected from the group consisting of N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl pyrrolidone, dimethylsulfoxide,sulfolane, glycol ethers, and the like.

18. The method of aspect 17, wherein the polar aprotic solvent isN,N-dimethylformamide.

19. The method of any one of aspects 1 to 18, wherein the chlorinationis carried out at a temperature of 100° C. or below.

20. The method of aspect 19, wherein the chlorination is carried out ata temperature of 85° C. or below.

21. The method of aspect 20, wherein the reaction mixture is heated to atemperature not exceeding 85° C. after contacting the carbohydrate withthe chlorinating agent.

22. The method of any one of aspects 1 to 21, wherein hydrogen chlorideis irreversibly removed from the reaction mixture by an irreversiblephysical process.

23. The method of aspect 22, wherein the irreversible physical processcomprises applying vacuum or sonic energy to, or inducing cavitationinto, the reaction mixture, or distilling off solvent with HCl.

24. The method of aspect 23, wherein the vacuum is applied when thereaction is mixture is being heated from a temperature of 50° C. orhigher.

25. The method of aspect 24, wherein the vacuum is applied until all orsubstantially all of the sucrose-6-ester is consumed.

26. The method of any one of aspects 23 to 25, wherein the vacuum isapplied for a period of about 5 minutes to about 12 hours.

27. The method of aspect 26, wherein the vacuum is applied for a periodof 30 minutes to about 2 hours.

28. The method of aspect 23, wherein the distillation is carried outwith or without vacuum.

29. The method of any one of aspects 1 to 21, wherein hydrogen chlorideis irreversibly removed from the reaction mixture by an irreversiblechemical process.

30. The method of aspect 29, wherein the irreversible chemical processcomprises reacting hydrogen chloride with a material that forms aproduct that contains covalently bonded chlorine atom.

31. The method of aspect 30, wherein the material is a cyclic ether oran olefin.

32. The method of aspect 31, wherein the cyclic ether is propyleneoxide.

33. The method of any one of aspects 1 to 32, further comprisingproviding a moisture free gas atmosphere over the reaction mixture orsparging a moisture free gas through the reaction mixture.

34. The method of aspect 33, wherein the moisture free gas is nitrogen,argon, helium, or air.

35. The method of any one of aspects 1 to 34, further comprisingcontacting the reaction mixture with an adsorbent for hydrochloric acid.

36. The method of aspect 35, wherein the adsorbent is placed in ascrubbing vessel located external to the chlorinating reactor.

37. The method of aspect 36, wherein the adsorbent comprises an acidscavenger.

38. The method of aspect 36 or 37, wherein the adsorbent or acidscavenger is selected from the group consisting of zeolites, activatedcarbon, organic amines, and polymeric resins.

39. A method for chlorinating a carbohydrate or a derivative thereofcomprising:

-   -   (i) dissolving the carbohydrate or derivative thereof in a polar        or non-polar aprotic solvent to obtain a solution of the        carbohydrate or derivative thereof;    -   (ii) forming a chlorinating agent in and/or combining a        pre-formed chlorinating agent in a solvent followed by        dissolution of carbohydrate or derivative thereof to obtain a        chlorination mixture;    -   (iii) irreversibly removing all or substantially all of the        hydrogen chloride produced during reaction of the chlorinating        agent with the hydroxy group or groups of the carbohydrate        and/or during chlorination of the carbohydrate or derivative        thereof;    -   (iv) optionally heating the reaction mixture from (iii) under an        inert gas atmosphere to a temperature of 60° C. for a period of        about 2 hours or more; and    -   (v) optionally heating the reaction mixture to a temperature not        more than 85° C., for a period of up to 16 hours, to obtain the        chlorinated carbohydrate or derivative thereof.

40. The method of aspect 39, wherein the irreversible removal of thehydrogen chloride produced during chlorination of the carbohydrate orderivative thereof is carried out by an irreversible physical processand/or an irreversible chemical process.

41. The method of aspect 40, wherein the irreversible removal is carriedout in an irreversible physical process.

42. The method of aspect 41, wherein the irreversible physical processcomprises applying vacuum or sonic energy or sparging a moisture freegas over the reaction mixture, inducing cavitation into the reactionmixture, or distilling off solvent with HCl.

43. The method of aspect 40, wherein the irreversible removal is carriedout in an irreversible chemical process or a physical process carriedout external to the chlorinating reactor.

44. The method of aspect 43, wherein the irreversible chemical processcomprises reacting the hydrogen chloride with a material that forms aninert chlorinated product.

45. The method of aspect 43, wherein the physical process comprisesscrubbing hydrogen chloride on an adsorbent placed in a scrubbing vessellocated external to the chlorinating reactor.

46. The method of any one of aspects 39 to 45, wherein the chlorinatedcarbohydrate or derivative thereof is chlorinated sucrose-6-ester.

47. The method of aspect 46, wherein the chlorinated sucrose-6-esterproduced is free or substantially free of charred residues.

48. The method of aspect 46 or 47, wherein the yield ofsucralose-6-ester is at least 65%.

49. A method of preparing sucralose comprising de-esterifying thechlorinated sucrose 6-ester obtained according to any one of aspects 1to 48 to obtain the sucralose.

50. Sucralose prepared by the method of aspect 49, which is free orsubstantially free of charred impurities.

51. Sucralose prepared by the method of aspect 49, which is free orsubstantially free of overchlorinated impurities.

1. A method for chlorinating a carbohydrate or a derivative thereofcomprising reacting the carbohydrate or derivative thereof with achlorinating agent and irreversibly removing during chlorination thehydrogen chloride produced by the reaction of the chlorinating agentwith the carbohydrate or derivative thereof.
 2. The method of claim 1,wherein the carbohydrate or derivative thereof is a sugar or derivativethereof.
 3. The method of claim 2, wherein the sugar derivative is asugar ester.
 4. The method of claim 3, wherein the sugar ester is asucrose-6-ester.
 5. The method of claim 4, wherein the chlorinatedproduct obtained is 4,1′,6′-trichloro-4,1′,6′-trideoxy-6-O-ester ofgalactosucrose (TGS-6E).
 6. The method of claim 1, wherein thechlorinating agent is an acid chloride or bis(trichloromethyl)carbonate.7. The method of claim 1, wherein the chlorinating agent is a VilsmeierReagent having the formula: [XYC=N⁺R₂]Cl⁻, wherein X is hydrogen, aryl,or alkyl, wherein the aryl or alkyl is optionally substituted with ahalogen, alkoxy, thioalkoxy, amido, or cyano; Y is a leaving group; andR is hydrogen or alkyl which is optionally substituted with halogen,alkoxy, thioalkoxy, amido, or cyano. 8-10. (canceled)
 11. The method ofclaim 7, wherein the Vilsmeier Reagent is produced by the reaction ofN,N-dimethylformamide with an acid chloride.
 12. The method of claim 11,wherein the acid chloride is selected from the group consisting ofthionyl chloride, sulfuryl chloride, phosgene, phosphorus pentachloride,oxalyl chloride, and methanesulfonyl chloride.
 13. The method of claim1, wherein the chlorination reaction is carried out in a polar solvent.14. The method of claim 13, wherein the polar aprotic solvent isselected from the group consisting of N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl pyrrolidone, dimethylsulfoxide,sulfolane, and glycol ethers.
 15. The method of claim 1, wherein thechlorination is carried out at a temperature of 85° C. or below.
 16. Themethod of claim 1, wherein the hydrogen chloride is irreversibly removedfrom the reaction mixture by an irreversible physical process.
 17. Themethod of claim 16, wherein the irreversible physical process comprisesapplying vacuum or sonic energy to, or inducing cavitation into, thereaction mixture, or distilling off solvent with HCl.
 18. The method ofclaim 17, wherein the vacuum is applied when the reaction is mixture isbeing heated from a temperature of 50° C. or higher. 19-25. (canceled)26. A method for chlorinating a carbohydrate or a derivative thereofcomprising: (i) dissolving the carbohydrate or derivative thereof in apolar or non-polar aprotic solvent to obtain a solution of thecarbohydrate or derivative thereof; (ii) forming a chlorinating agent inand/or combining a pre-formed chlorinating agent in a solvent followedby dissolution of carbohydrate or derivative thereof to obtain achlorination mixture; (iii) irreversibly removing during chlorinationall or substantially all of the hydrogen chloride produced by thereaction of the chlorinating agent with the hydroxy group or groups ofthe carbohydrate and/or the carbohydrate or derivative thereof; (iv)optionally heating the reaction mixture from (iii) under an inert gasatmosphere to a temperature of 60° C. for a period of about 2 hours ormore; and (v) optionally heating the reaction mixture to a temperaturenot more than 85° C., for a period of up to 16 hours, to obtain thechlorinated carbohydrate or derivative thereof.
 27. The method of claim26, wherein the irreversible removal of the hydrogen chloride is carriedout by an irreversible physical process and/or an irreversible chemicalprocess.
 28. The method of claim 27, wherein the irreversible removal iscarried out in an irreversible physical process.
 29. The method of claim28, wherein the irreversible physical process comprises applying vacuumor sonic energy or sparging a moisture free gas over the reactionmixture, inducing cavitation into the reaction mixture, or distillingoff solvent with HCl.
 30. The method of claim 28, wherein theirreversible removal is carried out in an irreversible chemical processor a physical process carried out external to the chlorinating reactor.